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Saikosaponin B1 and Saikosaponin D inhibit tumor growth in medulloblastoma allograft mice via inhibiting the Hedgehog signaling pathway

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Abstract

Medulloblastoma (MB), accounting for nearly 10% of all childhood brain tumors, are implicated with aberrant activation of the Hedgehog (Hh) signaling pathway. Saikosaponin B1 (SSB1) and Saikosaponin D (SSD), two bioactive constituents of Radix Bupleuri, are reported to have many biological activities including anticancer activities. In our work, we evaluated the inhibition of SSB1 and SSD on MB tumor growth in allograft mice and explored the underlying mechanisms. The associated biological activity was investigated in Shh Light II cells, an Hh-responsive fibroblast cell line, using the Dual-Glo® Luciferase Assay System. First, SSB1 (IC50, 241.8 nM) and SSD (IC50, 168.7 nM) inhibited GLI-luciferase activity in Shh Light II cells stimulated with ShhN CM, as well as Gli1 and Ptch1 mRNA expression. In addition, both compounds suppressed the Hh signaling activity provoked by smoothened agonist (SAG) or excessive Smoothened (SMO) expression. Meanwhile, SSB1 and SSD did not inhibit glioma-associated oncogene homolog (GLI) luciferase activity activated by abnormal expression of downstream molecules, suppressor of fuse (SUFU) knockdown or GLI2 overexpression. Consequently, SSB1 (30 mg/kg, ip) and SSD (10 mg/kg, ip) displayed excellent in vivo inhibitory activity in MB allografts, and the tumor growth inhibition ratios were approximately 50% and 70%, respectively. Our findings, thus, identify SSB1 and SSD significantly inhibit tumor growth in MB models by inhibiting the Hedgehog pathway through targeting SMO.

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References

  1. Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432:324–331

    Article  CAS  Google Scholar 

  2. Bale AE (2002) Hedgehog signaling and human disease. Annu Rev Genom Hum Genet 3:47–65

    Article  CAS  Google Scholar 

  3. Ingham PW, McMahon AP (2001) Hedgehog signaling in animal development: paradigms and principles. Genes Dev 15:3059–3087

    Article  CAS  Google Scholar 

  4. Robbins DJ, Fei DL, Riobo NA (2012) The Hedgehog signal transduction network. Sci Signal 5:6

    Article  Google Scholar 

  5. Rimkus TK, Carpenter RL, Qasem S, Chan M, Lo HW (2016) Targeting the sonic Hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers (Basel). https://doi.org/10.3390/cancers8020022

    Article  Google Scholar 

  6. Norsworthy KJ, By K, Subramaniam S, Zhuang L, Del Valle PL, Przepiorka D, Pazdur R (2019) FDA approval summary: glasdegib for newly diagnosed acute myeloid leukemia. Clin Cancer Res 25:6021–6025

    Article  CAS  Google Scholar 

  7. Northcott PA, Robinson GW, Kratz CP, Mabbott DJ, Pomeroy SL, Clifford SC, Pfister SM (2019) Medulloblastoma. Nat Rev Dis Primers 5:11

    Article  Google Scholar 

  8. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472

    Article  CAS  Google Scholar 

  9. Garcia-Lopez J, Kumar R, Smith KS, Northcott PA (2021) Deconstructing sonic Hedgehog medulloblastoma: molecular subtypes, drivers, and beyond. Trends Genet 37:235–250

    Article  CAS  Google Scholar 

  10. Robinson GW, Orr BA, Wu G, Gururangan S, Lin T, Qaddoumi I, Gajjar A (2015) Vismodegib exerts targeted efficacy against recurrent sonic Hedgehog-subgroup medulloblastoma: results from phase II pediatric brain tumor consortium studies PBTC-025B and PBTC-032. J Clin Oncol 33:2646–2654

    Article  CAS  Google Scholar 

  11. Ma H, Yokoyama S, Saiki I, Hayakawa Y (2017) Chemosensitizing effect of saikosaponin B on B16F10 melanoma cells. Nutr Cancer 69:505–511

    Article  CAS  Google Scholar 

  12. Ren D, Luo J, Li Y, Zhang J, Yang J, Liu J, Xin H (2020) Saikosaponin B2 attenuates kidney fibrosis via inhibiting the Hedgehog pathway. Phytomedicine 67:153163

    Article  CAS  Google Scholar 

  13. Maity T, Fuse N, Beachy PA (2005) Molecular mechanisms of Sonic Hedgehog mutant effects in holoprosencephaly. Proc Natl Acad Sci USA 102:17026–17031

    Article  CAS  Google Scholar 

  14. Taipale J, Chen JK, Cooper MK, Wang B, Mann RK, Milenkovic L, Beachy PA (2000) Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406:1005–1009

    Article  CAS  Google Scholar 

  15. Yang J, Wang J, Liu Y, Zhang Y, Huang W, Zou Y, Tan W (2021) PGE2-JNK signaling axis non-canonically promotes Gli activation by protecting Gli2 from ubiquitin-proteasomal degradation. Cell Death Dis 12:707

    Article  CAS  Google Scholar 

  16. Eichberger T, Sander V, Schnidar H, Regl G, Kasper M, Schmid C, Frischauf AM (2006) Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics 87:616–632

    Article  CAS  Google Scholar 

  17. Chen JK, Taipale J, Young KE, Maiti T, Beachy PA (2002) Small molecule modulation of Smoothened activity. Proc Natl Acad Sci USA 99:14071–14076

    Article  CAS  Google Scholar 

  18. Bar EE, Chaudhry A, Farah MH, Eberhart CG (2007) Hedgehog signaling promotes medulloblastoma survival via Bc/II. Am J Pathol 170:347–355

    Article  CAS  Google Scholar 

  19. Lu CN, Yuan ZG, Zhang XL, Yan R, Zhao YQ, Liao M, Chen JX (2012) Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-κB signaling pathway. Int Immunopharmacol 14:121–126

    Article  CAS  Google Scholar 

  20. Waszak SM, Northcott PA, Buchhalter I, Robinson GW, Sutter C, Groebner S, Pfister SM (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785–798

    Article  CAS  Google Scholar 

  21. Sasai K, Romer JT, Lee Y, Finkelstein D, Fuller C, McKinnon PJ, Curran T (2006) Shh pathway activity is down-regulated in cultured medulloblastoma cells: implications for preclinical studies. Cancer Res 66:4215–4222

    Article  CAS  Google Scholar 

  22. Taipale J, Cooper MK, Maiti T, Beachy PA (2002) Patched acts catalytically to suppress the activity of Smoothened. Nature 418:892–897

    Article  CAS  Google Scholar 

  23. Li X, Li X, Huang N, Liu R, Sun R (2018) A comprehensive review and perspectives on pharmacology and toxicology of saikosaponins. Phytomedicine 50:73–87

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (No. 81573655), Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University (Traditional Chinese Pharmacology), Zhejiang Chinese Medical University (No. ZYAOX2018002).

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Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, People’s Republic of China

    Jia Luo, Juan Wang, Jun Yang, Wenjing Huang, Wenfu Tan & Hong Xin

  2. Laboratory of Medicinal Plant Biotechnology, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, People’s Republic of China

    Junqiu Liu

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  1. Jia Luo
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  2. Juan Wang
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  3. Jun Yang
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  7. Hong Xin
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Correspondence to Wenfu Tan or Hong Xin.

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Luo, J., Wang, J., Yang, J. et al. Saikosaponin B1 and Saikosaponin D inhibit tumor growth in medulloblastoma allograft mice via inhibiting the Hedgehog signaling pathway. J Nat Med 76, 584–593 (2022). https://doi.org/10.1007/s11418-022-01603-8

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  • DOI: https://doi.org/10.1007/s11418-022-01603-8

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